Compensatory regulation of body weight in response to physiologic insult ensures proper maintenance of energy homeostasis, but these compensatory mechanisms are largely uncharacterized. We previously generated transgenic mice in which Agouti- related protein (Agrp) neurons were progressively degenerated. These mice exhibited a mild feeding and weight phenotype compared with mice in which Agrp neurons are acutely ablated. We have obtained preliminary data to show that neurogenesis is increased specifically in the hypothalamus of adult mutant mice and that some of the proliferating cells take on Agrp neuronal cell fate. In this proposal, we will evaluate whether de novo neurogenesis serves as a functional compensatory mechanism to regulate energy homeostasis. We will investigate whether orexigenic Agrp neurons are preferentially generated relative to anorexigenic cell types in the mutant hypothalamus. Further, we will examine whether the newly generated cells are capable of responding to leptin by activating signal transducer and activator of transcription 3 (Stat3). Finally, to determine whether de novo neurogenesis serves as a functional compensatory mechanism, we will block cell proliferation in the hypothalamus of the control and mutant mice and observe whether anorexia and body weight loss are induced only in the mutant mice. The proposed studies will provide direct evidence that neurogenesis may serve as a novel compensatory mechanism to regulate energy balance and ameliorate the effects of physiological insult during development and adulthood. (Lay language relevance of this research to public health): Obesity prevalence has increased dramatically in the United States, and is a major risk factor for type 2 diabetes, cardiovascular diseases, and other health problems. Research outlined in this proposal will help better understand how body weight is normally regulated, and how obesity develops. The identification of neuronal substrates critical for body weight regulation will lay the groundwork for future therapeutic interventions designed to target these specific neurons. [unreadable] [unreadable] [unreadable]